WO2017133683A1 - 一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e及其制备方法和用途 - Google Patents

一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e及其制备方法和用途 Download PDF

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WO2017133683A1
WO2017133683A1 PCT/CN2017/072890 CN2017072890W WO2017133683A1 WO 2017133683 A1 WO2017133683 A1 WO 2017133683A1 CN 2017072890 W CN2017072890 W CN 2017072890W WO 2017133683 A1 WO2017133683 A1 WO 2017133683A1
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Prior art keywords
compound
formula
maleate salt
crystal
crystalline
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PCT/CN2017/072890
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English (en)
French (fr)
Chinese (zh)
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丁照中
孙飞
胡迎虎
周义龙
王峥
杨玲
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正大天晴药业集团股份有限公司
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Priority to AU2017215800A priority Critical patent/AU2017215800B2/en
Priority to US16/075,080 priority patent/US10780091B2/en
Priority to SG11201806682TA priority patent/SG11201806682TA/en
Priority to UAA201809085A priority patent/UA123781C2/uk
Priority to EA201891770A priority patent/EA038794B1/ru
Priority to MX2018009500A priority patent/MX374295B/es
Priority to JP2018540750A priority patent/JP6898336B2/ja
Priority to MYPI2018702706A priority patent/MY196762A/en
Priority to PH1/2018/501644A priority patent/PH12018501644B1/en
Priority to KR1020187024626A priority patent/KR102393279B1/ko
Priority to CA3013682A priority patent/CA3013682C/en
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to HK19101224.5A priority patent/HK1259175B/zh
Priority to DK17747003.6T priority patent/DK3412671T3/da
Priority to BR112018015881-0A priority patent/BR112018015881B1/pt
Priority to CN201780009746.0A priority patent/CN108602830B/zh
Priority to NZ745231A priority patent/NZ745231A/en
Priority to ES17747003T priority patent/ES2834303T3/es
Priority to EP17747003.6A priority patent/EP3412671B1/en
Publication of WO2017133683A1 publication Critical patent/WO2017133683A1/zh
Priority to ZA2018/05185A priority patent/ZA201805185B/en
Priority to IL260965A priority patent/IL260965B/en
Priority to US16/991,639 priority patent/US20200368241A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medicinal chemistry.
  • the present invention relates to a maleate salt of a TLR7 agonist, a process for the preparation thereof, a pharmaceutical composition comprising the salt, and uses thereof.
  • the present invention also relates to the crystalline form C, the crystalline form D, the crystalline form E of the above salt, a process for preparing the same, a crystalline composition comprising the crystalline form, a pharmaceutical composition comprising the crystalline form or crystalline composition, and a pharmaceutical composition thereof use.
  • Toll-like receptors are expressed by a variety of immune cells. Toll-like receptors recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMP) expressed by microbial pathogens or damage-associated molecular patterns (DAMP) released by necrotic cells. Activation of the signal cascade by stimulation of Toll-like receptors by the corresponding PAMP or DAMP results in activation of transcription factors such as AP-1, NF- ⁇ B and interferon regulatory factors (impulse response functions). This results in a variety of cellular responses, including the production of interferons, pro-inflammatory cytokines and effector cytokines, thereby eliciting an immune response. To date, 13 Toll-like receptors have been found in mammals.
  • PAMP pathogen-associated microbial patterns
  • DAMP damage-associated molecular patterns
  • Toll-like receptors 1, 2, 4, 5, and 6 are predominantly expressed on the cell surface, while Toll-like receptors 3, 7, 8, and 9 are expressed in endosomes.
  • Different Toll-like receptors can recognize ligands derived from different pathogens.
  • Toll-like receptor 7 (TLR7) is mainly expressed by plasmacytoid dendritic cells (pDC) and induces secretion of interferon alpha (IFN- ⁇ ) by ligand recognition.
  • Toll-like receptor 7 (TLR7) and Toll-like receptor 8 (TLR8) are highly homologous, and thus the TLR7 ligand is in many cases also a TLR8 ligand.
  • TLR8 stimulation primarily induces the production of cytokines such as tumor necrosis factor alpha (TNF-alpha) and chemokines.
  • TNF-alpha tumor necrosis factor alpha
  • Interferon alpha is one of the main drugs for the treatment of chronic hepatitis B or hepatitis C, while TNF- ⁇ is a pro-inflammatory cytokine whose excessive secretion may cause serious side effects.
  • TLR7 agonists have been reported to date, such as Imiquimod (British Journal of Dermatology 2003; 149 (Suppl. 66): 5-8), Resiquimod, Antiviral Research 64 (2004) 79 –83), GS-9620 (Gastroenterology (2013), 144(7), 1508-1517), but there is still a great need for new TLR7 agonists with better selectivity, activity and safety.
  • the invention provides a maleate salt of a compound of formula I:
  • the invention provides a crystalline form of a maleate salt of a compound of formula I, and a corresponding method of preparation and crystalline composition thereof.
  • the crystalline form is Form C, Form D or Form E.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • the invention provides a pharmaceutical composition comprising one or more crystalline forms of the invention or crystalline compositions thereof.
  • the pharmaceutical composition may also optionally comprise a pharmaceutically acceptable carrier, excipient and/or vehicle.
  • the present invention provides a method of treating or preventing a Toll-like Receptor 7 (TLR7)-related disease, the method comprising administering to an individual in need thereof an effective amount of a crystalline form of the present invention or a crystal thereof A composition or pharmaceutical composition.
  • TLR7 Toll-like Receptor 7
  • the disease is a viral infection.
  • the invention also provides the use of a crystalline form of the invention, or a crystalline composition or pharmaceutical composition thereof, for the manufacture of a medicament for the treatment or prevention of a Toll-like receptor 7 (TLR7)-related disease.
  • TLR7 Toll-like receptor 7
  • the disease is a viral infection.
  • the invention also provides a crystalline form of the invention, or a crystalline composition or pharmaceutical composition thereof, for use in the treatment or prevention of a Toll-like receptor 7 (TLR7)-related disease.
  • TLR7 Toll-like receptor 7
  • the disease is a viral infection.
  • the viral infection is a hepatitis virus infection, in particular a hepatitis B or hepatitis C virus infection.
  • Figure 1 is an XRPD pattern of Form C of the maleate salt of the compound of Formula I.
  • Figure 2 is an XRPD pattern of Form D of the maleate salt of the compound of Formula I.
  • Figure 3 is an XRPD pattern of Form E of the maleate salt of the compound of Formula I.
  • pharmaceutical composition refers to an active ingredient, optionally in combination with one or more pharmaceutically acceptable chemical ingredients such as, but not limited to, carriers and/or excipients.
  • the active ingredient is, for example, a compound of formula I or a maleate thereof, one or more of the crystalline forms of the invention or one or more of the crystalline compositions of the invention.
  • pharmaceutically acceptable carrier refers to those carriers which have no significant irritation to the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” means an inert substance which, together with the active ingredient, which facilitates administration of the active ingredient, including, but not limited to, acceptable for human or animal use as permitted by the State Food and Drug Administration (eg Any of the glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, Isotonicity agent, solvent or emulsifier.
  • Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, and the like.
  • Other about the carrier For information, reference may be made to Remington: The Science and Practice of Pharmacy, 21 st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • the term "excipient” generally refers to the vehicle, diluent and/or medium, etc. required to formulate an effective pharmaceutical composition.
  • administering refers to a method by which a compound or composition can be delivered to a desired biological site of action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like.
  • the term "effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • the "effective amount" of an active substance in the composition can be the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective to treat or prevent a target disorder, disease or condition.
  • the term may refer to, for example, one or more of the compounds of formula I or their maleates, one or more of the crystalline forms of the invention or the crystalline compositions of the invention.
  • the diffraction pattern obtained from crystalline compounds is often characteristic for a particular crystal form, where the relative intensity of the band (especially at low angles) may be due to crystallization.
  • the dominant orientation effect due to the difference in conditions, particle size, and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystal form to be targeted.
  • the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°, typically about ⁇ 0.1°. Therefore, this error should be taken into account when determining each crystal structure. If the crystalline form of the invention is described as being substantially as specified in the drawings, the term "substantially” is also intended to encompass such variability in the diffraction peak position.
  • d represents the crystal plane distance
  • ⁇ is Diffraction angle.
  • the peak positions of the XRPD spectrum have similarities as a whole, and the relative intensity error may be large.
  • some of the diffraction lines are missing due to factors such as a decrease in content. At this time, it is not necessary to rely on all the bands observed in the high-purity sample, and even one band may be given.
  • the crystals are characteristic.
  • DSC Differential Scanning Calorimetry
  • DSC differential scanning calorimetry
  • crystalline composition refers to a solid form comprising one or more crystalline forms of the invention (eg, Forms C, D, and/or E).
  • the amount of the crystalline form contained in the crystalline composition may each independently be 50% or more, 80% or more, 90% or more, or 95% or more.
  • the crystalline composition may optionally comprise other crystalline forms or other amorphous forms of a compound of formula I or a salt thereof (such as a maleate) or an impurity other than these.
  • a salt thereof such as a maleate
  • the present invention provides a maleate salt of a compound of formula I:
  • the molar ratio of the compound of formula I to maleic acid in the maleate salt of the compound of formula I is from 1:1 to 3, preferably 1:2.
  • the maleate salt of the compound of formula I of the present invention can be prepared by a conventional maleate salt preparation process.
  • XRPD X-ray diffraction
  • XRPD X-ray diffraction
  • the diffraction peak of Form C of the maleate salt of the compound of Formula I has the following characteristics:
  • the X-ray powder diffraction pattern of Form C of the maleate salt of the compound of Formula I is substantially as shown in FIG.
  • Form C can also be characterized by DSC with an onset temperature of 97.0 ° C ⁇ 5 ° C and a peak temperature of 106.0 ° C ⁇ 5 ° C.
  • the molar ratio of the compound of formula I to the maleic acid in Form C is from 1:1 to 3, preferably 1:2.
  • the present invention also provides a process for the preparation of Form C, which comprises precipitating a maleate salt of a compound of Formula I from a solvent.
  • the method comprises the steps of:
  • the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, ethyl acetate and a mixed solvent thereof; preferably ethanol.
  • the amount of the solvent to be added per 1 mol of the compound of the formula I is 0.2 to 8 L, preferably 0.3 to 4 L, more preferably 0.5 to 2 L, and most preferably 1 L.
  • the heating temperature may be from 40 ° C to 90 ° C, preferably from 50 ° C to 80 ° C, more preferably from 70 ° C to 80 ° C.
  • the amount of the maleic acid to be added per 1 mol of the compound of the formula I is 1.0 to 4 mol, preferably 1.6 to 3.0 mol, more preferably 2.0 to 2.4 mol, most preferably 2.2 mol.
  • the invention further relates to a crystalline composition comprising the crystalline form C.
  • Form C comprises 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more by weight of the crystalline composition.
  • the crystalline composition in addition to Form C, may comprise other crystalline or amorphous forms of the compound of Formula I or a salt thereof or impurities other than these.
  • XRPD X-ray diffraction
  • XRPD X-ray diffraction
  • XRPD X-ray diffraction
  • the diffraction peak of Form D of the maleate salt of the compound of Formula I has the following characteristics:
  • the X-ray powder diffraction pattern of Form D of the maleate salt of the compound of Formula I is substantially as shown in FIG.
  • Form D can also be characterized by DSC with an onset temperature of 98.3 ° C ⁇ 5 ° C and a peak temperature of 110.1 ° C ⁇ 5 ° C.
  • the molar ratio of the compound of formula I to the maleic acid in Form D is from 1:1 to 3, preferably 1:2.
  • the invention also provides a method of preparing Form D, the method comprising the steps of:
  • the amount of the crystal form C of the maleate salt per 1 g of the compound of the formula I is 2 to 30 mL, preferably 8 to 24 mL, more preferably 12 to 20 mL, still more preferably 14 to 16 mL.
  • the constant temperature is 20 to 60 ° C, preferably 30 to 50 ° C, more preferably 35 to 45 ° C, still more preferably 40 ° C.
  • the invention further relates to a crystalline composition comprising the crystalline form D.
  • Form D is crystalline.
  • the composition has a weight of 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more.
  • the crystalline composition in addition to Form D, may comprise other crystalline or amorphous forms of the compounds of formula I or salts thereof or impurities other than these.
  • XRPD X-ray diffraction
  • XRPD X-ray diffraction
  • the diffraction peak of Form E of the maleate salt of the compound of Formula I has the following characteristics:
  • the X-ray powder diffraction pattern of Form E of the maleate salt of the compound of Formula I is substantially as shown in FIG.
  • Form E of the present invention can also be characterized by DSC with an onset temperature of 85.7 ° C ⁇ 5 ° C and a peak temperature of 97.5 ° C ⁇ 5 ° C.
  • the molar ratio of the compound of formula I to the maleic acid in Form E is from 1:1 to 3, preferably 1:2.
  • the invention also provides a method of preparing Form E, the method comprising the steps of:
  • the crystal C of the maleate salt per 1 g of the compound of the formula I corresponds to the amount of isopropanol added in an amount of 2 to 30 mL, preferably 8 to 24 mL, more preferably 12 to 20 mL, further preferably 14 to 16 mL. .
  • the constant temperature is 20 to 60 ° C, preferably 30 to 50 ° C, more preferably 35 to 45 ° C, still more preferably 40 ° C.
  • the invention further relates to a crystalline composition comprising the crystalline form E.
  • Form E is greater than 50% by weight of the crystalline composition, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more.
  • the crystalline composition, in addition to Form E, may comprise other crystalline or amorphous forms of the compound of Formula I or a salt thereof or impurities other than these.
  • the present invention provides a pharmaceutical composition comprising an effective amount of a maleate salt of a compound of formula I; Form C or a crystalline composition comprising said Form C; Form D or comprising said Form D Crystalline composition; or Form E or a crystalline composition comprising the Form E, or any combination thereof.
  • the pharmaceutical compositions may or may not contain pharmaceutically acceptable carriers, excipients, and/or vehicles.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a salt thereof with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet, a pill, or a capsule.
  • a suitable pharmaceutically acceptable carrier for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet, a pill, or a capsule.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • Typical routes of administration of a compound of the invention or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, Intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers, excipients and/or vehicles which are well known in the art. These carriers, excipients and vehicles enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients. Dosing.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, fillers such as sugars including lactose, sucrose, mannitol Or sorbitol; cellulose preparations such as microcrystalline cellulose, corn starch, wheat starch, rice starch and potato starch; and other substances such as silica gel, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose , hydroxymethylcellulose sodium and / or polyvinylpyrrolidone; disintegrating agents, such as sodium carboxymethyl starch, croscarmellose sodium, cross-linked polyvinylpyrrolidone, agar or alginic acid, may also use salts, such as Sodium alginate.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • the crystal form C, the crystal form D and the crystal form E of the maleate salt of the compound of the formula I of the invention have the advantages of high purity, high crystallinity, good stability, and the like, and are suitable for preparation for preventing or treating Toll-like samples.
  • Drug for body 7 (TLR7) related diseases are included in the crystal form C, the crystal form D and the crystal form E of the maleate salt of the compound of the formula I of the invention.
  • a pharmaceutical composition comprising an effective amount of a maleate salt of a compound of the formula I as described in the paragraph [1] or [2].
  • the disease is a viral infection, in particular a hepatitis virus infection, such as a hepatitis B or hepatitis C virus infection.
  • the solvent in the step 1) is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, Acetone, ethyl acetate or a mixed solvent thereof.
  • the heating temperature may be selected from 40 ° C to 90 ° C, preferably 50 ° C to 80 ° C, and more. It is preferably 70 ° C to 80 ° C.
  • a pharmaceutical composition comprising an effective amount of the crystalline form C as described in any of paragraphs [6] to [10] or the crystalline composition according to the paragraph [17].
  • the disease is a viral infection, in particular a hepatitis virus infection, such as a hepatitis B or hepatitis C virus infection.
  • the crystal form D according to any one of paragraphs [21] to [24], characterized in that, when characterized by DSC, the starting temperature of the crystal form D is 98.3 ° C ⁇ 5 ° C, the peak value The temperature was 110.1 ° C ⁇ 5 ° C.
  • the constant temperature is 20 to 60 ° C, preferably 30 to 50 ° C, more preferably 35 ⁇ 45 ° C, more preferably 40 ° C.
  • a pharmaceutical composition comprising an effective amount of the crystalline form D as described in any of paragraphs [21] to [25] or the crystalline composition according to the paragraph [29].
  • the disease is a viral infection, in particular a hepatitis virus infection, such as a hepatitis B or hepatitis C virus infection.
  • Form E according to any one of the paragraphs [33]-[35], wherein the Form E has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the amount of the isopropanol added per 1 g of the maleic acid salt of the compound of the formula I is 2 to 2 30 mL, preferably 8 to 24 mL, more preferably 12 to 20 mL, most preferably 14 to 16 mL.
  • the constant temperature is 20 to 60 ° C, preferably 30 to 50 ° C, more preferably 35 to 45 ° C, More preferably, it is 40 °C.
  • a pharmaceutical composition comprising an effective amount of the crystalline form E as described in any of paragraphs [33] to [37] or the crystalline composition according to paragraph [41].
  • the disease is a viral infection, in particular a hepatitis virus infection, such as a hepatitis B or hepatitis C virus infection.
  • SEM-Cl for 2-(trimethylsilyl)ethoxymethyl chloride
  • SEM for 2-(trimethylsilyl)ethoxymethyl
  • DIPEA for diisopropylethylamine
  • TFA stands for trifluoroacetic acid
  • DMF stands for N,N-dimethylformamide
  • n-BuOH stands for n-butanol
  • NH 3 ⁇ H 2 O stands for ammonia water
  • Na stands for sodium metal
  • XRPD stands for X-ray powder diffraction
  • DSC stands for difference Thermal analysis.
  • the compound of formula II (2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine) (4.00 kg, 21.28 mol) was dissolved in DMF (20.00 L) and batched at room temperature (25 ° C) DIPEA (2.58 kg, 20.00 mol) was added followed by stirring for 30 min.
  • the reaction liquid was cooled to 0 ° C with an ice bath, and then SEM-Cl (4.00 kg, 24.00 mol) was slowly added dropwise at a dropping rate of 1-2 drops/sec over 5 hours. After completion of the dropwise addition, the reaction solution was stirred at 0 ° C for 4 hours. The reaction was monitored by HPLC.
  • the compound of formula V (1.10 kg, 3.27 mol) was dissolved in TFA (5.50 L) and the reaction was stirred at 25 ° C for 16 h.
  • the reaction was monitored by HPLC, the TFA was evaporated under reduced pressure, and the residue was dissolved in methanol (1.2 L) and ice water (1.2 L), and the mixture was adjusted to pH 12 with concentrated aqueous ammonia, then stirred for 2 hours. There are constant precipitations. After filtration, the filter cake was obtained as a white solid, which was purified from 15% aqueous ammonia (1.times.times.times.3) and ethyl acetate (4L) to give the compound of formula VI (550.00g, 2.67mol, 81.7%) as a white solid. .
  • the compound of the formula VIII (440.0 g, 1.11 mol) and dichloromethane (7.0 L) were placed in a 20 L reactor and stirred to cool the system to below -15 °C. After triethylsilane (880 mL, 5.55 mol) was added dropwise to the system, trifluoroacetic acid (880 mL) was further added dropwise, and the temperature was kept below -10 °C during the dropwise addition. After the completion of the dropwise addition, the reaction was carried out at 0 ° C for 2 hr, and the liquid phase was monitored until the starting point disappeared.
  • the reaction mixture was concentrated to dryness, and ethyl acetate (2.2 L) was added, and the mixture was cooled to below 0 °C.
  • the obtained cake was beaten with 2.2 L of water, filtered, and dried under reduced pressure to give 550 g of trifluoroacetic acid salt of the compound of formula I as a white solid.
  • the compound of formula I (3.80 g, 10 mmol) was added to 10 mL of ethanol and dissolved by heating. To the solution was added maleic acid (2.55 g, 22 mmol). The solution was then allowed to naturally cool to room temperature and allowed to stand for 1-2 hours. The precipitate was filtered, and the solid was dried under reduced pressure using an oil pump to give the compound of the formula I, the salt of the compound of the formula I. In the obtained maleate salt, the molar ratio of the compound of the formula I to maleic acid was 1:2.
  • maleate salt form C 50 mg was added 0.8 mL of acetone to form a suspension.
  • the suspension sample was shaken on a thermostat (40 ° C) for 2 days (protected from light).
  • the residual solid was centrifuged and dried overnight in a vacuum oven at 40 ° C to give the compound D of the compound of formula I in solid form.
  • the molar ratio of the compound of the formula I to maleic acid was 1:2.
  • maleate salt form C 50 mg was added 0.8 mL of isopropanol to form a suspension.
  • the suspension sample was shaken on a thermostat (40 ° C) for 2 days (protected from light).
  • the residual solid was centrifuged and dried overnight in a vacuum oven at 40 ° C to give the compound of formula I, maleate salt, E in solid form.
  • the molar ratio of the compound of the formula I to maleic acid was 1:2.
  • Forms C, D and E prepared in Examples 1-3 were placed in open clean containers, respectively, and placed at 60 ° C, and samples were taken on days 10, 20 and 30, respectively. The test results were compared with the initial test results on day 0.
  • the crystal forms C, D and E prepared in Examples 1-3 were respectively placed in a constant temperature and humidity container for accelerated test under the conditions of 40 ° C / 75% humidity (open), and samples were taken on the 30th, 60th and 90th days. Detection. Test results with day 0 The initial test results are compared.
  • Forms C, D, and E prepared in Examples 1-3 were each placed in a light environment of 5000 Lx ⁇ 500 Lx, and samples were taken on Days 5, 10, and 30. The test results were compared with the initial test results on day 0.
  • GS-9620 and R848 used are as follows, wherein GS-9620 can be prepared by the method disclosed in US20100143301; R848 is purchased from Baiqi Bio (Cat. No. IMG-2208, specification 0.5 mg).
  • the culture plate containing the cells and the compound was cultured in a CO 2 incubator for 24 hours under the conditions of 37 ° C, 5% CO 2 concentration.
  • the compound of formula I of the present invention exhibits higher in vitro receptor binding activity to Toll-like receptor 7 than the control (Toll-like receptor 7 agonist GS-9620), as well as the control substance ( Toll-like receptor 7 agonist GS-9620) has lower in vitro receptor binding activity to Toll-like receptor 8.
  • the compounds of the invention have significant selectivity differences for different receptors and are superior to the prior art.
  • the purpose of this example was to detect the expression level of cytokines after stimulating human peripheral blood mononuclear cells (PBMC) for 24 hours using the compound of formula I.
  • the cell supernatant was not diluted at the time of detection, and the level of IFN- ⁇ was directly detected.
  • the compound of formula I was first formulated into a 20 mmol concentration DMSO stock solution, and a 10-fold serial dilution of the cell culture medium was used to dilute a total of 11 points.
  • the compound with 9 dilution points (the highest concentration of compound was 200 ⁇ mol/L) was added to a 96-well plate at 50 ⁇ L per well, and then fresh human peripheral blood mononuclear cells were seeded, and each well was inoculated with 150 ⁇ L of system containing 450,000 cells. .
  • the cell culture plates were incubated for 24 hours at 37 ° C in a 5% CO 2 incubator.
  • the compounds of formula I of the present invention exhibit better IFN-[alpha]-inducing activity of PBMCs in vitro and TNF-[alpha]-inducing activity comparable to the control (GS-9620) compared to the control (GS-9620).

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PCT/CN2017/072890 2016-02-05 2017-02-04 一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e及其制备方法和用途 WO2017133683A1 (zh)

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CA3013682A CA3013682C (en) 2016-02-05 2017-02-04 Maleate salt of a pyrrolo[3,2-d]pyrimidine compound as tlr7 agonist and crystalline forms c, d and e thereof
SG11201806682TA SG11201806682TA (en) 2016-02-05 2017-02-04 Tlr7 agonist maleate salt, crystalline forms c, d and e thereof, preparation methods and uses of maleate salt and crystalline forms
UAA201809085A UA123781C2 (uk) 2016-02-05 2017-02-04 Малеатна сіль агоніста tlr7, її кристалічні форми c, d і e, способи одержання і застосування малеатної солі і кристалічних форм
EA201891770A EA038794B1 (ru) 2016-02-05 2017-02-04 Малеатная соль агониста tlr7, ее кристаллические формы c, d и e, способы получения и применение малеатной соли и кристаллических форм
MX2018009500A MX374295B (es) 2016-02-05 2017-02-04 Sal de maleato de agonista de tlr7, sus formas cristalinas c, d y e, sus métodos de preparación y usos de la sal de maleato y formas cristalinas.
JP2018540750A JP6898336B2 (ja) 2016-02-05 2017-02-04 Ｔｌｒ７アゴニストのマレイン酸塩、その結晶形ｃ、ｄ及びｅ、マレイン酸塩及び結晶形の調製方法及び使用
HK19101224.5A HK1259175B (zh) 2016-02-05 2017-02-04 一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e及其制备方法和用途
US16/075,080 US10780091B2 (en) 2016-02-05 2017-02-04 TLR7 agonist maleate salt, crystalline forms C, D and E thereof, preparation methods and uses of maleate salt and crystalline forms
KR1020187024626A KR102393279B1 (ko) 2016-02-05 2017-02-04 Tlr7 작용제 말레에이트 염, 이의 결정형 c, d 및 e, 말레에이트 염 및 결정형의 제조 방법 및 용도
AU2017215800A AU2017215800B2 (en) 2016-02-05 2017-02-04 TLR7 agonist maleate salt, crystalline forms C, D and E thereof, preparation methods and uses of maleate salt and crystalline forms
PH1/2018/501644A PH12018501644B1 (en) 2016-02-05 2017-02-04 Tlr7 agonist maleate salt, crystalline forms c, d and e thereof, preparation methods and uses of maleate salt and crystalline forms
MYPI2018702706A MY196762A (en) 2016-02-05 2017-02-04 Tlr7 agonist maleate salt, crystalline forms c, d and e thereof, preparation methods and uses of maleate salt and crystalline forms
DK17747003.6T DK3412671T3 (da) 2016-02-05 2017-02-04 TLR7-agonist-maleatsalt, krystallinske former C, D og E deraf, fremgangsmåder til fremstilling og anvendelser af maleatsalt og krystallinske former
BR112018015881-0A BR112018015881B1 (pt) 2016-02-05 2017-02-04 Sal de maleato de agonista de tlr7, formas cristalinas, c, d e e, seusprocessos de preparação e seus usos, e composições cristalina efarmacêutica
CN201780009746.0A CN108602830B (zh) 2016-02-05 2017-02-04 一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e及其制备方法和用途
NZ745231A NZ745231A (en) 2016-02-05 2017-02-04 Tlr7 agonist maleate salt, crystalline forms c, d and e thereof, preparation methods and uses of maleate salt and crystalline forms
ES17747003T ES2834303T3 (es) 2016-02-05 2017-02-04 Sal de maleato de agonista de TLR7, formas cristalinas C, D y E de la misma, métodos de preparación y usos de la sal de maleato y las formas cristalinas
EP17747003.6A EP3412671B1 (en) 2016-02-05 2017-02-04 Tlr7 agonist maleate salt, crystalline forms c, d and e thereof, preparation methods and uses of maleate salt and crystalline forms
ZA2018/05185A ZA201805185B (en) 2016-02-05 2018-08-01 Tlr7 agonist maleate salt, crystalline forms c, d and e thereof, preparation methods and uses of maleate salt and crystalline forms
IL260965A IL260965B (en) 2016-02-05 2018-08-02 The malate salt as an agonist of tlr7, its c, d and e crystal structures, preparation methods and uses of the malate salt and the crystal structures
US16/991,639 US20200368241A1 (en) 2016-02-05 2020-08-12 Tlr7 agonist maleate salt, crystalline forms c, d and e thereof, preparation methods and uses of maleate salt and crystalline forms

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020162705A1 (ko) 2019-02-08 2020-08-13 성균관대학교산학협력단 톨-유사 수용체 7 또는 8 작용자와 콜레스테롤의 결합체 및 그 용도
WO2021177679A1 (ko) 2020-03-02 2021-09-10 성균관대학교산학협력단 병원균 외벽 성분 기반 생병원체 모방 나노 입자 및 그 제조 방법
WO2022031057A1 (ko) 2020-08-04 2022-02-10 성균관대학교산학협력단 활성화 부위가 일시적으로 비활성화된 톨-유사 수용체 7 또는 8 작용자와 기능성 약물의 결합체 및 그 용도
WO2022031021A1 (ko) 2020-08-04 2022-02-10 성균관대학교산학협력단 동력학적 제어가 가능한 아주번트를 포함하는 mrna 백신
WO2022031011A1 (ko) 2020-08-04 2022-02-10 성균관대학교산학협력단 동력학적으로 작용하는 아주번트 앙상블

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107043379A (zh) 2016-02-05 2017-08-15 正大天晴药业集团股份有限公司 一种tlr7激动剂的晶型a、其制备方法和医药用途
CN107043380A (zh) 2016-02-05 2017-08-15 正大天晴药业集团股份有限公司 一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e、制备方法和用途
CN107043378A (zh) * 2016-02-05 2017-08-15 正大天晴药业集团股份有限公司 一种吡咯并[3,2-d]嘧啶类化合物的制备方法及其中间体
KR20210013183A (ko) * 2018-05-25 2021-02-03 치아타이 티안큉 파마수티컬 그룹 주식회사 Tlr7 작용제 및 폐암을 치료하기 위한 이의 약학 조합물

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104780924A (zh) * 2012-11-20 2015-07-15 葛兰素史克有限责任公司 新颖的化合物
CN104780923A (zh) * 2012-11-20 2015-07-15 葛兰素史克有限责任公司 新颖的化合物
CN104837840A (zh) * 2012-10-10 2015-08-12 爱尔兰詹森科学公司 用于治疗病毒感染及其他疾病的吡咯并[3,2-d]嘧啶衍生物
WO2015168269A1 (en) * 2014-05-01 2015-11-05 Novartis Ag Compounds and compositions as toll-like receptor 7 agonists
WO2016023511A1 (zh) * 2014-08-15 2016-02-18 正大天晴药业集团股份有限公司 作为tlr7激动剂的吡咯并嘧啶化合物

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3376479B2 (ja) * 1991-08-12 2003-02-10 武田薬品工業株式会社 縮合ピリミジン誘導体、その製造法および用途
DE69731823T2 (de) 1996-07-03 2005-12-15 Sumitomo Pharmaceuticals Co., Ltd. Neue purinderivate
EP1035123B1 (en) 1997-11-28 2003-08-20 Sumitomo Pharmaceuticals Company, Limited Novel heterocyclic compounds
WO2007024707A2 (en) 2005-08-22 2007-03-01 The Regents Of The University Of California Tlr agonists
CA2691444C (en) 2007-06-29 2016-06-14 Gilead Sciences, Inc. Purine derivatives and their use as modulators of toll-like receptor 7
EP2188280B1 (en) 2007-08-03 2011-03-09 Pfizer Limited Imidazopyridinones
CN102272134B (zh) * 2008-12-09 2013-10-16 吉里德科学公司 Toll样受体调节剂
US9139590B2 (en) * 2011-02-04 2015-09-22 Duquesne University Of The Holy Spirit Bicyclic and tricyclic pyrimidine tyrosine kinase inhibitors with antitubulin activity and methods of treating a patient
EP2800569B1 (en) * 2012-01-05 2018-07-25 Northeastern University Allosteric modulators of cb1 cannabinoid receptors
BR112015011400A8 (pt) * 2012-11-20 2019-10-01 Glaxosmithkline Llc composto, composição farmacêutica, composição de vacina, e, uso de um composto
CN106029668B (zh) 2014-02-20 2018-02-23 葛兰素史克知识产权第二有限公司 吡咯并[3,2]嘧啶衍生物作为人类干扰素诱导剂
EA032487B1 (ru) * 2014-05-01 2019-06-28 Новартис Аг Соединения и композиции в качестве агонистов toll-подобного рецептора 7
CN105367576A (zh) * 2014-08-15 2016-03-02 正大天晴药业集团股份有限公司 作为tlr7激动剂的吡咯并嘧啶化合物
CN105732635A (zh) 2014-12-29 2016-07-06 南京明德新药研发股份有限公司 一类Toll样受体7激动剂
HUE052770T2 (hu) 2015-11-05 2021-05-28 Chia Tai Tianqing Pharmaceutical Group Co Ltd 7-(Tiazol-5-il)pirrolopirimidin vegyület mint TLR7 agonista
TWI714661B (zh) 2015-11-05 2021-01-01 法商賽諾菲公司 新穎念珠藻素化合物及接合物、其製備與其治療用途
PE20181453A1 (es) 2015-11-05 2018-09-12 Basf Se Oxadiazoles sustituidos para combatir hongos fitopatogenos
CN107043379A (zh) * 2016-02-05 2017-08-15 正大天晴药业集团股份有限公司 一种tlr7激动剂的晶型a、其制备方法和医药用途
CN107043380A (zh) 2016-02-05 2017-08-15 正大天晴药业集团股份有限公司 一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e、制备方法和用途
CN107043377A (zh) * 2016-02-05 2017-08-15 正大天晴药业集团股份有限公司 一种tlr7激动剂的三氟乙酸盐、晶型b及其制备方法、药物组合物和用途
CN107043378A (zh) 2016-02-05 2017-08-15 正大天晴药业集团股份有限公司 一种吡咯并[3,2-d]嘧啶类化合物的制备方法及其中间体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104837840A (zh) * 2012-10-10 2015-08-12 爱尔兰詹森科学公司 用于治疗病毒感染及其他疾病的吡咯并[3,2-d]嘧啶衍生物
CN104780924A (zh) * 2012-11-20 2015-07-15 葛兰素史克有限责任公司 新颖的化合物
CN104780923A (zh) * 2012-11-20 2015-07-15 葛兰素史克有限责任公司 新颖的化合物
WO2015168269A1 (en) * 2014-05-01 2015-11-05 Novartis Ag Compounds and compositions as toll-like receptor 7 agonists
WO2016023511A1 (zh) * 2014-08-15 2016-02-18 正大天晴药业集团股份有限公司 作为tlr7激动剂的吡咯并嘧啶化合物

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020162705A1 (ko) 2019-02-08 2020-08-13 성균관대학교산학협력단 톨-유사 수용체 7 또는 8 작용자와 콜레스테롤의 결합체 및 그 용도
WO2021177679A1 (ko) 2020-03-02 2021-09-10 성균관대학교산학협력단 병원균 외벽 성분 기반 생병원체 모방 나노 입자 및 그 제조 방법
WO2022031057A1 (ko) 2020-08-04 2022-02-10 성균관대학교산학협력단 활성화 부위가 일시적으로 비활성화된 톨-유사 수용체 7 또는 8 작용자와 기능성 약물의 결합체 및 그 용도
WO2022031021A1 (ko) 2020-08-04 2022-02-10 성균관대학교산학협력단 동력학적 제어가 가능한 아주번트를 포함하는 mrna 백신
WO2022031011A1 (ko) 2020-08-04 2022-02-10 성균관대학교산학협력단 동력학적으로 작용하는 아주번트 앙상블

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